Registration Conditions of Morinda Officinalis How Oligosaccharide Capsule
Morinda officinalis How is the root of Rubiaceae Radix Morindae Officinalis plants. Academy of Military Medical Sciences and Beijing Tong Ren Tang Group Co., Ltd. have developed five new pure-plant anti-depression drugs jointly, and it is the second pure-plant anti-depression drug in the global. The author has identified seven monomeric compounds in Morinda Officinalis How Oligosaccharide Capsule, a kind of water extract of Morinda Officinalis How, related to antidepressant-like activity, with the use of extraction, dialysis, multiple column chromatography isolation, and chemical and spectroscopy structural analysis means. Such compounds are a group of inulin-type oligosaccharide and their physical and chemical property and biological activity are similar, and they make up anti-depression activity part in water extract of Morinda Officinalis How. In vegetable drug screening in early 90s, people found that oligosaccharide extracts of Morinda Officinalis How may have anti-depression effects, which were proved in multiple animal and vitro experiment model. Researches show that their effective components are inulin-type oligosaccharide, namely oligosaccharide aggressiveness is made up of one glucose and two to six fructoses. 3-5 glycan is a sweetening agent, food additives, or functional food in foreign countries. Morinda Officinalis How Oligosaccharide possesses major 4-7 fructosan, which is the major effective component of anti depression. Experimental results show that Morinda Officinalis How Oligosaccharide not only has anti-depression effects on different animal models but also is very low in toxicity. It was found with anti-depression effects for the first time at researching pharmacological actions of Morinda Officinalis How Oligosaccharide with the use of modern pharmacology. It can notably improve many physical signs of reserpine mice through boosting reduced nerve monoamine transmitters contents in reserpine mice brain. Pharmacological researches show that pharmacodynamics activity is notable in classical depression animal models, such as tail suspension and forced swimming etc. And at the same time, researches show that they have effects on anti-stress and impotence, which can improve depressed patients’ state of unselfishness and low sexual function. Intensive studies show that Morinda Officinalis How Oligosaccharide can enhance rats’ brain endodermis and mRNA expression of sea horse Gs protein α subunit, strengthen adenylate cyclase activity of cortex, sea horse, and hypothalamus under activated state, boost neurotrophic factor expression in rat brain, and protect neuron damage or apoptosis induced by corticosterone. The function of Morinda Officinalis How Oligosaccharide is the same as classical tricyclic antidepressant Desipramine, which may be one of action mechanisms of classical tricyclic antidepressant Desipramine. Acute toxicity and chronic toxicity researches don’t find obvious toxic reactions related to drugs.
Preclinical studies of Morinda Officinalis How Oligosaccharide Capsule have been completed by Academy of Military Medical Sciences and Beijing Tong Ren Tang Group Co., Ltd. jointly. Taiyuan Chengcheng Pharmaceutical Co., Ltd. initiated ten national drug clinical trial institutions to conduct clinical studies in 2006, registered it in China Food and Drug Administration; it completed production registration in May, 2012, launched in domestic and foreign markets in the same year, and conducted phase-IV clinical studies in 2014 again.Specifications of Morinda Officinalis How Oligosaccharide Capsule:
it is a capsule, whose active ingredients are Morinda Officinalis How Oligosaccharide. Each capsule contains 300mg bulk drug of Morinda Officinalis How Oligosaccharide.Quality standards of Morinda Officinalis How Oligosaccharide Capsule:
worked out quality standard drafts of Morinda Officinalis How Oligosaccharide Capsule for clinical use. The product shall contain at least 25mg/piece for effective parts of Morinda Officinalis How Oligosaccharide (counted as 3-9 aggressiveness of inulin-type oligosaccharide, and those containing 5 aggressiveness of inulin-type oligosaccharide shall not be less than 3mg/piece. The method under the identification can state existence of Morinda Officinalis How Oligosaccharide. Inspection items meet relevant provisions in appendixes of Chinese Pharmacopoeia (2000). The determination method is high-performance liquid chromatography, which can measure disturbances accurately, sensitively, and specifically and control the product’s quality effectively.
Research results for stability of Morinda Officinalis How Oligosaccharide Capsule:
Morinda Officinalis How Oligosaccharide Capsule shall be investigated for 12 months at room temperature after sealed with aluminum foil blister. If Morinda Officinalis How Oligosaccharide Capsule doesn’t change in appearance or content, it is qualified. Therefore, the product is favorable in stability. Its period of validity is two years temporarily.
Phase-I clinical research reviews:
Research period: from February, 2006 to March, 2006, completed by Peking University Sixth Hospital (Peking University Mental Health Institute).
Research objectives: to discuss security and tolerance of Morinda Officinalis How Oligosaccharide Capsule after taking it for seven days, in the way of 50-1000mg (six dosage groups) for one time and 800mg/times/day for several times and to provide theoretical bases for dose determination, drug delivery routes, dose treatment course, and formulation of dosage regimen for phase-II clinical test.
The number of subjects: 42 in all: 21 males and 21 females (single dose group: 16 males and 16 females; multi-dose group: 5 males and 5 females).
Results: researches on 42 subjects have been finished completely, without clinical adverse events, electrocardiograms, laboratory tests, or vital signs.
Phase-II clinical research reviews:
Research period: from May, 2006 to February, 2007, completed by six drug clinical trial institutions jointly, 361 cases in all (119 cases for high does group, 121 cases for low dose group, and 121 cases for the control group). Through data blind review, 356 subjects enter into FAS crowd (119 cases for high dose group, 119 cases for low dose group, and 118 cases for the control group), 343 subjects enter into PP crowd (116 cases for high dose group, 114 cases for low dose group, and 113 cases for the control group), and 18 subjects are rejected.
Research results: evaluate curative effects after six weeks with the use of Hamilton’s Depression Scale (≥50％): the effective rate of the control group is 70.34%; the effective rate of high dose group is 66.39%; the effective rate of the low dose group is 68.91%; comparison among such three groups doesn’t have statistical significances (P>0.05); CMHχ2 inspection results of central hierarchy show that differences among high dose group, low dose group, and the control group don’t have statistical significances (P>0.05). Non-inferiority tests of two groups of rate differences are qualified (P<0.05).
Safety evaluation: conclusions on security indexes and comprehensive evaluations of adverse reactions: there are 73 adverse events related to researched drugs in the whole test process, including 30 adverse events for high dose group, 20 adverse events for low dose group, and 23 adverse events for the control group, which are the same as those in reported values when compared with adverse reaction rate of fluoxetine tablets. Major of adverse reactions of Morinda Officinalis How Oligosaccharide Capsule are nausea, swirl, thirst, and constipation, but it doesn’t affect drugs for clinical tests or damage subjects’ health, which indicates that investigational products don’t have side effects under therapeutic dose.
Phase-III clinical test reviews:
Research period: from March, 2007 to January, 2008. It is completed by nine drug clinical trial institutions jointly. 613 cases in all: 587 cases in FSA dataset, including 351 cases for test group, 117 cases for the control group, 119 cases for placebo group; 574 cases in PP dataset, including 346 cases for test group, 112 cases for the control group, and 116 for placebo group, and 39 cases are rejected.
Research results: evaluate curative effects after six weeks with the use of Hamilton’s Depression Scale (≥50％): FAS dataset: the effective rate of the control group is 72.65%, the effective rate of test group is 71.23%, and the effective rate of placebo group is 36.97%; PP dataset: the effective rate of the control group is 75.89%, the effective rate of test group is 72.25%, and the effective rate of placebo group is 37.93%. Comparison among such three groups has statistical significances (P<0.01). CMHχ2 inspection results of central hierarchy show that differences among high dose group, low dose group, and the control group have statistical significances (P<0.01). Non-inferiority tests of two groups of rate differences are qualified (P<0.05). Morinda Officinalis How Oligosaccharide Capsule isn’t inferior to clinical fluoxetine tablets.
Safety evaluation: there are 118 adverse events related to researched drugs in the whole test process, accounting for 19.25% of the total samples, including 64 cases for test group, 28 cases for the control group, and 26 cases for placebo group. There are two serious adverse events irrelevant to investigational products.
Research conclusions: (1) curative effects of Morinda Officinalis How Oligosaccharide Capsule curing depression are superior to that of placebo, not inferior to fluoxetine; (2) curative effects of Morinda Officinalis How Oligosaccharide Capsule towards TCM syndrome are superior to fluoxetine; (3) Morinda Officinalis How Oligosaccharide Capsule is effective to anxiety accompanying with depression; (4) adverse reactions of Morinda Officinalis How Oligosaccharide Capsule under therapeutic dose are light, good in safety.
It acquired production registration document of China Food and Drug Administration in May, 2012. Furthermore, we continue to conduct reevaluation clinical researches after stage-IV lists in the market (required by Chinese regulations).
Market prospects: it is the first new anti-depression drug extracted from plants in China (the second in the global), adapting to treatment of depression. It has been accepted by all large and medium-scale hospitals, providing new therapeutic drug for depressed patients. As a kind of mental drug, it is a prescription drug according to provisions of The Drug Administration Law of the People’s Republic of China, which shall not enter into OTC market. The product’s annual profit is RMB 120 million after listing for two years. With market development, its GDP and profits will increase yearly, and we predict that its GDP will reach up to RMB 1 billion. At present, Beijing Tong Ren Tang Group Co., Ltd. is devoting to expanding its overseas market, preparing for registration before entering to the European Market, in accordance with drug administration laws and regulations of various countries in Europe.
Services offered by Cheng Cheng Pharmaceutical
In order to register and list a new drug, we shall be familiar with polices and regulations of China Food and Drug Administration and technical regulation requirements, evaluate risks (failure in registration) and profits (success in registration) after making full understanding of preclinical research materials, and provide feasible analysis plans for enterprises.
Organizing and initiating national authoritative drug clinical trial institutions (units) to develop phase-I, II, and III clinical researches, Cheng Cheng Pharmaceutical will tail after each subject and assist researchers (doctors) in testing subjects in blood cell, liver, renal function, urine, and electrocardiogram; researchers shall evaluate curative effects of subjects with the use of HAMD17 scale, nationally recognized. Cheng Cheng Pharmaceutical assigns clinical research associates (CRA) and clinical research coordinators (CRC) to track the whole research process, so as to guarantee research quality.
Clinical research application materials are information carriers used in the whole process and results of human trials, including policies and regulations, professional knowledge of mental health, schematic design of clinical researches, data analysis of clinical tests, safety evaluation, and research conclusions, which are approval documents of very important. Such documents will accept professional skill reviews of New Drug Evaluation Center of China Food and Drug Administration, which will decide whether such products can be approved or not.
In accordance with provisions for laws and regulations of China Food and Drug Administration, the product is a class-5 new drug and shall accept stage-IV clinical research reevaluation after listing, so as to provide bases for re-registration of official production documents.
It is necessary to provide literatures and the product’s technical data for the enterprise to expand the market.
Service procedures of Cheng Cheng Pharmaceutical Co., Ltd.
1. Sign a commission contract;
2. The entrusted party, Cheng Cheng Pharmaceutical Co., Ltd., accepts relevant documents of the product of Beijing Tong Ren Tang Group Co., Ltd., namely clinical trial permission documents of China Food and Drug Administration, preclinical research data (including research topic bases), pharmacodynamics data, acute toxicity test materials, and long-term toxicity test materials.
3. Provide risk assessment reports;
4. Provide clinical research plans;
5. Screen national drug clinical trial institutions (hospitals);
6. Write clinical trial schemes and design and research medical history and CRF tables, investigators’ brochures, and informed consent forms;
7. Organize to initiate multi-center clinical research start committee and training committee;
8. Sign a commission contract with the branch center and start branch center’s clinical research;
9. Assign CRA and CRC to track the whole research process;
10. Conduct statistic analysis on clinical researches and write research reports;
11. Write approval materials;
12. Submit approval materials for Beijing Tong Ren Tang Group Co., Ltd. and report to New Drug Review Center of China Food and Drug Administration;
13. Acquire production and registration approved documents.